We propose that a novel cluster of microRNAs (miRNAs) in the most frequently deleted genomic region associated with prostate cancer (PCa) repress epithelial-mesenchymal transition (EMT) and PCa progression and metastasis. EMT, a complex cellular program whereby epithelial tumor cells lose their epithelial polarity and gain mesenchymal phenotypes, is considered a critical step in invasion and metastases. The role of miRNAs in prostate cancer EMT and metastasis is largely unknown. We first identified that miR-203 represses EMT and PCa metastasis by directly targeting ZEB2 and other EMT regulators. Our recent data suggests that a cluster of miRNA genes on chromosome 8p21 (miR-3622a, 3622b, 4287, 4288) act as critical negative regulators of EMT in PCa. Loss of chromosome 8p21 is a frequent alteration in the prostate oncogenome, particularly in advanced PCa suggesting its role in PCa progression. It has been postulated that this region harbors alternative tumor suppressor genes, the identity of which have largely remained elusive. We have identified a cluster of novel miRNA genes (miR-3622a, 3622b, 4287, 4288) that are located in this region that have never been explored. Our analysis suggests that these miRNAs regulate EMT and PCa progression and metastasis by directly targeting key EMT regulators including the SNAIL and ZEB family of transcription factors. In view of this, we propose that a cluster of miRNA genes at the frequently deleted chromosome 8p21 region function coordinately to repress the EMT program by directly targeting EMT inducing factors, thereby preventing prostate cancer progression and metastasis. We hypothesize that these miRNAs inhibit EMT by maintaining the epithelial phenotype through a direct inhibition of transcriptional repressors of E-cadherin including members of the SNAIL and ZEB family and thereby inhibit PCa progression and metastasis. We will test this hypothesis, under the following specific aims - Specific Aim I: Investigate the role of proposed miRNAs in frequently deleted genomic region in regulation of EMT and PCa progression and metastasis using both in vitro and in vivo models. Specific Aim II: Determine whether expression profiling of proposed EMT-regulating miRNAs in chromosome 8p21 region have associated prognostic and diagnostic potential in prostate cancer. Specific Aim III: Investigate the molecular basis of repression of EMT regulating miRNAs in prostate cancer. This project is highly novel and significant as it will potentially integrate the impact of common genomic deletions observed in prostate cancer with the EMT and metastatic program, an aspect that has never been explored. In particular, characterization of miRNA genes at chromosome 8p21 region will be a highly significant step forward in the field of prostate cancer Accomplishment of this project will uncover novel miRNA-mediated molecular pathways that drive PCa progression and metastasis with potential clinical implications in design of better prognostic and therapeutic strategies for advanced prostate cancer.